Genet Med. 2026 Oct 3:102741. doi: 10.1016/j.gim.2026.102741. Online ahead of print.
ABSTRACT
PURPOSE: Marfan syndrome, Loeys-Dietz syndrome, and heritable thoracic aortic aneurysms and dissections (hTAAD) are autosomal dominant connective-tissue disorders with overlapping features and considerable genetic variability. Many cases arise from pathogenic variants affecting extracellular matrix (ECM) components or TGFβ signaling, yet a substantial proportion of hTAAD cases remain genetically unexplained. This study aimed to identify new genetic contributors to aortic disease and to clarify their molecular and clinical impact.
METHODS: Exome and genome sequencing of a French cohort with syndromic or isolated hTAAD revealed rare damaging variants in ADAMTS6 in four unrelated individuals.
RESULTS: Functional analyses showed that these variants impaired ADAMTS6 secretion and catalytic activity, disrupting the processing of fibrillin-1 and fibrillin-2, leading to abnormal ECM accumulation and disorganized microfibrils. The recurrent p.(Leu814Arg) variant additionally altered Hippo and TGFβ signaling and affected cell adhesion. Patient-derived fibroblasts and Adamts6-deficient mice exhibited parallel pathological defects, supporting ADAMTS6 loss-of-function as disease-causing Clinically, presentations ranged from early-onset multisystem disease with cardiovascular, skeletal, craniofacial, and neurodevelopmental abnormalities to isolated adult-onset aortic aneurysm.
CONCLUSION: these findings establish ADAMTS6 deficiency as a newly recognized connective-tissue disorder with heart defects, aortic aneurysm, and neurodevelopmental features, highlighting ADAMTS6's key role in ECM integrity.
PMID:42829835 | DOI:10.1016/j.gim.2026.102741